ClinVar Miner

Submissions for variant NM_004329.2(BMPR1A):c.1433G>A (p.Arg478His) (rs113849804)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 11
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000131658 SCV000186685 uncertain significance Hereditary cancer-predisposing syndrome 2018-04-19 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000034701 SCV000043148 variant of unknown significance not provided 2012-07-13 no assertion criteria provided research Converted during submission to Uncertain significance.
Color RCV000131658 SCV000537586 likely benign Hereditary cancer-predisposing syndrome 2017-01-26 criteria provided, single submitter clinical testing
Counsyl RCV000203748 SCV000786297 uncertain significance Juvenile polyposis syndrome 2018-04-05 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000515344 SCV000611440 uncertain significance Juvenile polyposis syndrome; Hereditary mixed polyposis syndrome 2 2017-05-23 criteria provided, single submitter clinical testing
GeneDx RCV000034701 SCV000292499 uncertain significance not provided 2018-08-03 criteria provided, single submitter clinical testing This variant is denoted BMPR1A c.1433G>A at the cDNA level, p.Arg478His (R478H) at the protein level, and results in the change of an Arginine to a Histidine (CGT>CAT). This variant was observed in at least three individuals with colorectal cancer, two of whom were diagnosed at age 50 or younger (DeRycke 2017, Pearlman 2017, Yurgelun 2017), as well as in one individual with a personal history of a Lynch syndrome-associated cancer and/or colon polyps who was also found to carry a deletion of exons 1-9 in the EPCAM gene (Yurgelun 2015). This variant was also observed in a breast cancer patient and 1/572 individuals with atherosclerosis, with no specific information about cancer history (Johnston 2012, Tung 2015). BMPR1A Arg478His was observed at an allele frequency of 0.028% (36/126,734) in individuals of European ancestry in large population cohorts (Lek 2016). This variant is located in the protein kinase domain (UniProt). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether BMPR1A Arg478His is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000034701 SCV000698313 likely benign not provided 2016-10-06 criteria provided, single submitter clinical testing Variant summary: The BMPR1A c.1433G>A (p.Arg478His) variant involves the alteration of a conserved nucleotide. 4/5 in silico tools predict a damaging outcome for this variant. This variant was found in 17/121410 control chromosomes, predominantly observed in the European (Non-Finnish) subpopulation at a frequency of 0.0002248 (15/66738). This frequency is about 112 times the estimated maximal expected allele frequency of a pathogenic BMPR1A variant (0.000002), suggesting this is likely a benign polymorphism found primarily in the populations of European (Non-Finnish) origin. The variant was reported in the literature in individuals with unclear cancer phenotypes, and in two individuals tested for Lynch Syndrome, one of whom also carried a large deletion in EPCAM, which is likely responsible for the patients phenotype. Multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. Taken together, this variant is classified as likely benign.
Invitae RCV000203748 SCV000260786 uncertain significance Juvenile polyposis syndrome 2019-01-02 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 478 of the BMPR1A protein (p.Arg478His). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs113849804, ExAC 0.02%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been reported in an individual affected with colorectal cancer (PMID: 27978560) and an individual undergoing testing for Lynch syndrome (PMID: 25980754). ClinVar contains an entry for this variant (Variation ID: 41780). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000235579 SCV000712858 uncertain significance not specified 2016-12-28 criteria provided, single submitter clinical testing The p.Arg478His variant in BMPR1A has been reported in 1 individual with suspect ed Lynch Syndrome (Yurgelun 2015), 2 individuals who underwent exome sequencing for non-cancer related indications (Johnston 2012, D'Alessandro 2016) and has al so been reported in ClinVar (Variation ID 41780). This variant has also been ide ntified in 15/66738 of European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs113849804). Computational predict ion tools and conservation analysis suggest that the p.Arg478His variant may not impact the protein, though this information is not predictive enough to rule ou t pathogenicity. In summary, the clinical significance of the p.Arg478His varian t is uncertain.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000235579 SCV000600220 uncertain significance not specified 2016-08-30 criteria provided, single submitter clinical testing
University of Washington Department of Laboratory Medicine,University of Washington RCV000203748 SCV000886442 likely benign Juvenile polyposis syndrome 2018-04-30 criteria provided, single submitter research The BMPR1A variant designated as NM_004329.2:c.1433G>A (p.Arg478His) is classified as likely benign. This variant is listed in population databases and is found in approximately 1 out of 1750 individuals of European ancestry. In silico programs predict that this variant is likely to be tolerated (SIFT, Polyphen-2, Align-GVGD). In one observed family, this variant was not shown to segregate with colon polyps in family members who were over 60 years old. Bayesian analysis integrating all of this data (Tavtigian et al, 2018, PMID:29300386) gives approimately 1% probability of pathogenicity, which is consistent with a classification of likely benign. This variant is not predicted to alter BMPR1A function or modify cancer risk. A modest (less than 2 fold) increase in cancer risk due to this variant cannot be entirely excluded. This analysis was performed in conjunction with the family studies project as part of the University of Washington Find My Variant Study.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.